Targeting the complement system to improve radiation response
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
Our lab tries to understand how cancers exploit part of our immune system to their advantage. Our most recent work has focused on, the complement system, a part of the immune system that is best known for its role in helping fight infections. We have become very interested in this part of the immune system since cancer cells seem to hijack it for their own survival advantage. We are exploring the idea that cancer cells may be particularly dependent on these hijacked functions when exposed to external sources of damage, such as those used to kill the tumour during treatment. Our work indeed suggests that if we block certain parts of this system (with drugs) we may be able to make the cancer cell more likely to die following radiotherapy. Intriguingly, blocking certain parts of this system may also reduce the toxic effects of radiation in healthy gut. These findings therefore suggest that a drug against this system could reduce the side effects of radiation while also improving the effectiveness of radiotherapy on the tumour. We work to understand the details of how this works. The ultimate goal of these studies is to be able to use drugs against this system to improve radiotherapy in patients.
Technical Summary
Our lab studies how tumours exploit innate immune pathways to their advantage, using a combination of cancer patient data, in vitro experiments and in vivo models. We are particularly interested in how we can use these mechanistic insights to improve radiotherapy. Our most recent work has focused on the complement system, a central innate immunity pathway which we have found is frequently dysregulated in human cancers with poor prognoses. Importantly, our work suggests that, in response to radiotherapy, cancer cells may be particularly dependent on the functions of dysregulated complement for their survival. Indeed, pharmacological inhibition of certain members of the system can enhance the effects of radiation on the tumour. Intriguingly, our work also indicates that blocking certain members of the complement system can reduce side effects from radiotherapy. We are actively investigating the mechanisms underlying these beneficial effects. The ultimate goal of our research is to identify pharmacological targets that can improve the therapeutic index of radiotherapy and ultimately improve patient’s quality of life.
People |
ORCID iD |
Monica Olcina (Principal Investigator) |
Publications
Bader SB
(2021)
Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity.
in Nucleic acids research
Beach C
(2023)
Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.
in The Journal of clinical investigation
Beach C
(2022)
The effects of radiation therapy on the macrophage response in cancer.
in Frontiers in oncology
Krieg C
(2022)
Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy.
in Journal for immunotherapy of cancer
Moon EJ
(2022)
The importance of hypoxia in radiotherapy for the immune response, metastatic potential and FLASH-RT.
in International journal of radiation biology
O'Brien RM
(2023)
Thinking inside the box: intracellular roles for complement system proteins come into focus.
in British journal of cancer
Olcina MM
(2020)
Intracellular C4BPA Levels Regulate NF-?B-Dependent Apoptosis.
in iScience
Sodji QH
(2022)
The Combination of Radiotherapy and Complement C3a Inhibition Potentiates Natural Killer cell Functions Against Pancreatic Cancer.
in Cancer research communications
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00001/1 | 01/04/2017 | 31/03/2022 | £2,508,000 | ||
MC_UU_00001/2 | Transfer | MC_UU_00001/1 | 01/04/2017 | 31/03/2022 | £2,488,000 |
MC_UU_00001/3 | Transfer | MC_UU_00001/2 | 01/04/2017 | 31/05/2018 | £349,000 |
MC_UU_00001/4 | Transfer | MC_UU_00001/3 | 01/04/2017 | 31/03/2022 | £2,486,000 |
MC_UU_00001/5 | Transfer | MC_UU_00001/4 | 01/04/2017 | 30/09/2019 | £1,732,000 |
MC_UU_00001/6 | Transfer | MC_UU_00001/5 | 01/04/2017 | 31/03/2022 | £2,525,000 |
MC_UU_00001/7 | Transfer | MC_UU_00001/6 | 01/04/2017 | 31/03/2022 | £1,773,000 |
MC_UU_00001/8 | Transfer | MC_UU_00001/7 | 03/01/2019 | 31/03/2023 | £2,682,000 |
MC_UU_00001/9 | Transfer | MC_UU_00001/8 | 01/10/2019 | 31/03/2022 | £1,492,800 |
MC_UU_00001/10 | Transfer | MC_UU_00001/9 | 07/12/2020 | 31/03/2023 | £888,708 |
MC_UU_00001/11 | Transfer | MC_UU_00001/10 | 08/01/2021 | 31/03/2023 | £874,512 |
Description | Academy of Medical Sciences Springboard Award - Investigating C5aR1-mediated regulation of tumour cell death |
Amount | £99,998 (GBP) |
Organisation | Academy of Medical Sciences (AMS) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2023 |
End | 03/2025 |
Description | CRUK Oxford Centre Development Fund |
Amount | £4,996 (GBP) |
Funding ID | CRUKDF - 0221 - MO |
Organisation | Cancer Research UK |
Department | Cancer Research UK (CRUK) Oxford Centre |
Sector | Private |
Country | United Kingdom |
Start | 04/2021 |
End | 03/2022 |
Description | Radiation Research Network Project Seed Funding Award - IdentifyinG Radiotherapy and ImmunE ResistanCe Mechanisms In Anal CaNcer (GRECIAN) |
Amount | £147,779 (GBP) |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2023 |
End | 05/2024 |
Description | Access to ACRCelerate Colorectal cancer organoid and murine models |
Organisation | University of Oxford |
Department | Department of Oncology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Our group has provided expertise in the models available to study radiation-induced normal tissue toxicity in the gastrointestinal tract. This expertise resulted in our addition as co-applicants in a CRUK Experimental Medicine grant submission. My group also has a joint PhD student currently funded by ACRCelerate Colorectal Cancer Stratified Medicine Network consortium. This student is an active member of the laboratory who receives mentoring and training and who is expected to be a co-author on 3 publications this year. |
Collaborator Contribution | The DPhil student has contributed to in vivo and in vitro experiments using the models developed by the consortium. |
Impact | Invitation and participation at ACRCelerate Junior Researchers Symposium Publications in preparation. |
Start Year | 2021 |
Description | Access to ACRCelerate Colorectal cancer organoid and murine models |
Organisation | University of Oxford |
Department | Wellcome Trust Centre for Human Genetics |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | Our group has provided expertise in the models available to study radiation-induced normal tissue toxicity in the gastrointestinal tract. This expertise resulted in our addition as co-applicants in a CRUK Experimental Medicine grant submission. My group also has a joint PhD student currently funded by ACRCelerate Colorectal Cancer Stratified Medicine Network consortium. This student is an active member of the laboratory who receives mentoring and training and who is expected to be a co-author on 3 publications this year. |
Collaborator Contribution | The DPhil student has contributed to in vivo and in vitro experiments using the models developed by the consortium. |
Impact | Invitation and participation at ACRCelerate Junior Researchers Symposium Publications in preparation. |
Start Year | 2021 |
Description | I'm a Scientist Outreach |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | I'm a Scientist is an online, student-led science engagement activity where school students connect with working scientists. I am taking a leading role in organising an I'm a Scientist Outreach Zone centred around cancer research. This activity is expected to take place in the summer of 2022. It will include the participation of 5-10 researchers from our department. This will include a mixture of researchers, technicians and support staff to help show the range of roles it takes to do research and exposing students to a range of careers in science. |
Year(s) Of Engagement Activity | 2022 |
URL | https://about.imascientist.org.uk/category/zone-reports/ |
Description | UNIQ+ |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Undergraduate students |
Results and Impact | UNIQ+ internships and the Wellcome Biomedical Vacation Scholarships offer paid summer research experience over six weeks, from 4 July 2022. Participants will work on research projects with regular support and supervision from Oxford staff and students, as well as training in key research skills. The idea is to expose students from more diverse background to postgraduate studies and a career in science more generally. |
Year(s) Of Engagement Activity | 2022 |